Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site

Jinbin Xu; Chenbo Zeng; Wenhua Chu; Fenghui Pan; Justin M. Rothfuss; Fanjie Zhang; Zhude Tu; Dong Zhou; Dexing Zeng; Suwanna Vangveravong; Fabian Johnston; Dirk Spitzer; Katherine C. Chang; Richard S. Hotchkiss; William G. Hawkins; Kenneth T. Wheeler; Robert H. MacH

doi:10.1038/ncomms1386

Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site

Jinbin Xu, Chenbo Zeng, Wenhua Chu, Fenghui Pan, Justin M. Rothfuss, Fanjie Zhang, Zhude Tu, Dong Zhou, Dexing Zeng, Suwanna Vangveravong, Fabian Johnston, Dirk Spitzer, Katherine C. Chang, Richard S. Hotchkiss, William G. Hawkins, Kenneth T. Wheeler, Robert H. MacH

Research output: Contribution to journal › Article › peer-review

266 Scopus citations

Abstract

The sigma-2 receptor, whose gene remains to be cloned, has been validated as a biomarker for tumour cell proliferation. Here we report the use of a novel photoaffinity probe, WC-21, to identify the sigma-2 receptor-binding site. WC-21, a sigma-2 ligand containing both a photoactive azide moiety and a fluorescein isothiocyanate group, irreversibly labels sigma-2 receptors in rat liver; the membrane-bound protein was identified as PGRMC1 (progesterone receptor membrane component 1). Immunocytochemistry reveals that both PGRMC1 and SW120, a fluorescent sigma-2 receptor ligand, colocalize with molecular markers of the endoplasmic reticulum and mitochondria in HeLa cells. Overexpression and knockdown of the PGRMC1 protein results in an increase and a decrease in binding of a sigma-2 selective radioligand, respectively. The identification of the putative sigma-2 receptor-binding site as PGRMC1 should stimulate the development of unique imaging agents and cancer therapeutics that target the sigma-2 receptor/PGRMC1 complex.

Original language	English (US)
Article number	380
Journal	Nature communications
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/ncomms1386
State	Published - 2011
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Xu, J., Zeng, C., Chu, W., Pan, F., Rothfuss, J. M., Zhang, F., Tu, Z., Zhou, D., Zeng, D., Vangveravong, S., Johnston, F., Spitzer, D., Chang, K. C., Hotchkiss, R. S., Hawkins, W. G., Wheeler, K. T., & MacH, R. H. (2011). Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site. Nature communications, 2(1), [380]. https://doi.org/10.1038/ncomms1386

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title = "Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site",

abstract = "The sigma-2 receptor, whose gene remains to be cloned, has been validated as a biomarker for tumour cell proliferation. Here we report the use of a novel photoaffinity probe, WC-21, to identify the sigma-2 receptor-binding site. WC-21, a sigma-2 ligand containing both a photoactive azide moiety and a fluorescein isothiocyanate group, irreversibly labels sigma-2 receptors in rat liver; the membrane-bound protein was identified as PGRMC1 (progesterone receptor membrane component 1). Immunocytochemistry reveals that both PGRMC1 and SW120, a fluorescent sigma-2 receptor ligand, colocalize with molecular markers of the endoplasmic reticulum and mitochondria in HeLa cells. Overexpression and knockdown of the PGRMC1 protein results in an increase and a decrease in binding of a sigma-2 selective radioligand, respectively. The identification of the putative sigma-2 receptor-binding site as PGRMC1 should stimulate the development of unique imaging agents and cancer therapeutics that target the sigma-2 receptor/PGRMC1 complex.",

author = "Jinbin Xu and Chenbo Zeng and Wenhua Chu and Fenghui Pan and Rothfuss, {Justin M.} and Fanjie Zhang and Zhude Tu and Dong Zhou and Dexing Zeng and Suwanna Vangveravong and Fabian Johnston and Dirk Spitzer and Chang, {Katherine C.} and Hotchkiss, {Richard S.} and Hawkins, {William G.} and Wheeler, {Kenneth T.} and MacH, {Robert H.}",

note = "Funding Information: This study was supported by CA 102869, American Cancer Society MRSG 08-019-01CDD, VA Merit Award 1136919 and by the McDonnell Center for Systems Neuroscience at Washington University. We thank Dr Leslie M. Hicks, Ms Jeanne Speichinger and Ms Rebecca White for help with the matrix-assisted laser desorption/ ionization–mass spectrometry analysis and protein sequencing.",

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AU - Xu, Jinbin

AU - Zeng, Chenbo

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AU - Zhang, Fanjie

AU - Tu, Zhude

AU - Zhou, Dong

AU - Zeng, Dexing

AU - Vangveravong, Suwanna

AU - Johnston, Fabian

AU - Spitzer, Dirk

AU - Chang, Katherine C.

AU - Hotchkiss, Richard S.

AU - Hawkins, William G.

AU - Wheeler, Kenneth T.

AU - MacH, Robert H.

N1 - Funding Information: This study was supported by CA 102869, American Cancer Society MRSG 08-019-01CDD, VA Merit Award 1136919 and by the McDonnell Center for Systems Neuroscience at Washington University. We thank Dr Leslie M. Hicks, Ms Jeanne Speichinger and Ms Rebecca White for help with the matrix-assisted laser desorption/ ionization–mass spectrometry analysis and protein sequencing.

PY - 2011

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N2 - The sigma-2 receptor, whose gene remains to be cloned, has been validated as a biomarker for tumour cell proliferation. Here we report the use of a novel photoaffinity probe, WC-21, to identify the sigma-2 receptor-binding site. WC-21, a sigma-2 ligand containing both a photoactive azide moiety and a fluorescein isothiocyanate group, irreversibly labels sigma-2 receptors in rat liver; the membrane-bound protein was identified as PGRMC1 (progesterone receptor membrane component 1). Immunocytochemistry reveals that both PGRMC1 and SW120, a fluorescent sigma-2 receptor ligand, colocalize with molecular markers of the endoplasmic reticulum and mitochondria in HeLa cells. Overexpression and knockdown of the PGRMC1 protein results in an increase and a decrease in binding of a sigma-2 selective radioligand, respectively. The identification of the putative sigma-2 receptor-binding site as PGRMC1 should stimulate the development of unique imaging agents and cancer therapeutics that target the sigma-2 receptor/PGRMC1 complex.

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Identification of the PGRMC1 protein complex as the putative sigma-2 receptor binding site

Abstract

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